Hydrophobic Drug-Delivery Material, Method for Manufacturing Thereof and Methods for Delivery of a Drug-Delivery Composition

ABSTRACT

A method for manufacturing a drug-delivery composition includes providing at least a pharmaceutically active composition, providing a hydrophobic matrix; and mixing the hydrophobic matrix and the pharmaceutically active composition to form a paste-like or semi-solid drug-delivery composition.

FIELD OF THE INVENTION

The present invention belongs to the field of controlled drug release,particularly to methods for manufacturing drug-delivery compositionsincluding pharmaceutically active substances or compounds, and to thecontrolled delivery thereof into living organisms and tissues fortherapeutic purposes.

BACKGROUND OF THE INVENTION

Most therapeutic dosage forms include mixtures of one or more activepharmaceutical ingredients (APIs) with additional components referred toas excipients. APIs are substances that exert a pharmacological effecton a living tissue or organism, whether used for prevention, treatment,or cure of a disease. APIs can be naturally occurring or syntheticsubstances, or can be produced by recombinant methods, or anycombination of these approaches.

Numerous methods have been devised for delivering APIs into livingorganisms, each with more or less success. Traditional oral therapeuticdosage forms include both solids (tablets, capsules, pills, etc.) andliquids (solutions, suspensions, emulsions, etc.). Parenteral dosageforms include solids and liquids as well as aerosols (administered byinhalers, etc.), injectables (administered with syringes, micro-needlearrays, etc.), topicals (foams, ointments, etc.), and suppositories,among other dosage forms. Although these dosage forms might be effectivein delivering low molecular weight APIs, each of these various methodssuffers from one or more drawbacks, including the lack ofbioavailability as well as the inability to completely control eitherthe spatial or the temporal component of the API's distribution when itcomes to high molecular weight APIs. These drawbacks are especiallychallenging for administering biotherapeutics, i.e. pharmaceuticallyactive peptides (e.g. growth factors), proteins (e.g. enzymes,antibodies), oligonucleotides and nucleic acids (e.g. RNA, DNA, PNA,aptamers, spiegelmers), hormones and other natural substances orsynthetic substances mimicking such, since many types ofpharmacologically active biomolecules at least partially are broken downeither in the digestive tract or in the blood system and are deliveredsuboptimally to the target site.

Therefore, an ongoing need exists for improved drug-delivery methods inthe life sciences, including but not limited to human and veterinarymedicine. One important goal for any new drug-delivery method is todeliver the desired therapeutic agent(s) to a specific place in the bodyover a specific and controllable period of time, i.e. controlling thedelivery of one or more substances to specific organs and tissues in thebody in both a spatial and temporal manner. Methods for accomplishingthis spatially and temporally controlled delivery are known ascontrolled-release drug-delivery methods. Delivering APIs to specificorgans and tissues in the body offers several potential advantages,including increased patient compliance, extending activity, lowering therequired dose, minimizing side effects, and permitting the use of morepotent therapeutics. In some cases, controlled-release drug-deliverymethods can even allow the administration of therapeutic agents whichwould otherwise be too toxic or ineffective for use.

There are five broad types of solid dosage forms for controlled-deliveryoral administration: reservoir and matrix diffusive dissolution,osmotic, ion-exchange resins, and prodrugs. For parenterals, most of theabove solid dosage forms are available as well as injections(intravenous, intramuscular, etc.), transdermal systems, and implants.Numerous products have been developed for both oral and parenteraladministration, including depots, pumps, micro- and nano-particles.

The incorporation of APIs into polymer matrices acting as a corereservoir is one approach for controlling their delivery. Contemporaryapproaches for formulating such drug-delivery systems are dependent ontechnological capabilities as well as the specific requirements of theapplication. For sustained delivery systems there a two main structuralapproaches: the release controlled by diffusion through a barrier suchas shell, coat, or membrane, and the release controlled by the intrinsiclocal binding strength of the API(s) to the core or to other ingredientsin the core reservoir.

Another strategy for controlled delivery of therapeutic agents,especially for delivering biotherapeutics, involves their incorporationinto polymeric micro- and nano-particles either by covalent or cleavablelinkage or by trapping or adsorption inside porous network structures.Various particle architectures can be obtained, for instance core/shellstructures. Typically one or more APIs are contained either in the core,in the shell, or in both components. Their concentration can bedifferent throughout the respective component in order to modify therelease pattern. Although polymeric nano-spheres can be effective in thecontrolled delivery of APIs, they also suffer from severaldisadvantages. For example, their small size can allow them to diffusein and out of the target tissue or being successfully attacked bymacrophages. The use of intravenous nano-particles may also be limiteddue to rapid clearance by the reticuloendothelial system.Notwithstanding this, polymeric micro-spheres remain an importantdelivery vehicle.

In view of the above, there is a need for improving drug-deliverymethods and compositions.

SUMMARY OF THE INVENTION

According to an embodiment, a method for manufacturing a drug-deliverycomposition is provided. The method includes providing at least apharmaceutically active composition, including a hydrophobic matrix, anda liquid; and mixing the hydrophobic matrix and the pharmaceuticallyactive composition to form a paste-like or semi-solid drug-deliverycomposition.

According to an embodiment, a drug-delivery composition is provided,which comprises a paste-like or semi-solid mixture including at least ahydrophobic matrix and a pharmaceutically active compound.

According to an embodiment, a method for delivery a drug-deliverycomposition is provided. The method includes providing a drug-deliverycomposition including a paste-like or semi-solid mixture comprising atleast a hydrophobic matrix and a pharmaceutically active compound; andapplying the drug-delivery composition into a human or animal body.

Those skilled in the art will recognize additional features andadvantages upon reading the following detailed description, and uponviewing the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings are included to further an understanding ofthe embodiments that are incorporated in and constitute a part of thisspecification. The drawings illustrate embodiments and together with thedescription serve to explain principles of embodiments. Otherembodiments and many of the intended advantages of embodiments will bereadily appreciated, as they become better understood by reference tothe following detailed description. The elements of the drawings are notnecessarily to scale relative to each other.

FIG. 1 illustrates release of antibodies from hydrophobic matrices atroom temperature.

FIG. 2 illustrates release of antibody 2 from a hydrophobic matrix atbody temperature.

FIG. 3 shows a comparison between the mechanically treated antibody 3releasing hydrophobic matrix and self-organized antibody 3—releasinghydrophobic matrix.

DETAILED DESCRIPTION OF THE INVENTION

The following language and descriptions of certain preferred embodimentsof the present invention are provided in order to further anunderstanding of the principles of the present invention. However, itwill be understood that no limitations of the present invention areintended, and that further alterations, modifications, and applicationsof the principles of the present invention are also included.

For the purpose of this specification, the term “mixing” intends todescribe a mechanical process or a mechanical treatment of thecomponents. For example, mixing can be in the sense of carrying outrepeated cycles of pressing and folding or comparable processing stepswhich lead to an intense compression and mixing of the providedhydrophobic matrices. The pharmaceutically active components arereferred to hereinafter as active pharmaceutical ingredients (APIs).

According to an embodiment a drug-delivery composition is manufacturedby providing at least a pharmaceutically active composition or API;providing a hydrophobic matrix; and mixing the hydrophobic matrix andthe pharmaceutically active composition to form a paste-like orsemi-solid drug delivery composition. An advantage of such amanufacturing method consists in achieving a sustained releaseformulation for pharmaceutically active ingredients with improvedrelease characteristics. In particular, the method allows preparingdrug-delivery compositions for sustained release of ingredientscharacterized by a specific biological activity which otherwise mightdecrease or even terminate.

According to an embodiment a drug-delivery composition is manufactured,wherein providing the hydrophobic matrix comprises mixing at least ahydrophobic solid component and a hydrophobic liquid component.Advantageously by mixing a given liquid hydrophobic component with agiven solid hydrophobic component, allows preparing a wide range ofconsistencies i.e. rheological properties like viscosities of thepaste-like or semi-solid composition depending on their quantitativerelation. On the other hand, by carefully selecting a solid hydrophobiccomponent and a liquid hydrophobic component, similar consistencies i.e.rheological properties, like viscosities of the paste-like or semi-solidcomposition can be achieved. Furthermore, depending on the type andquantity of the selected APIs, different hydrophobic components can becombined in order to form a paste-like or semi-solid composition withthe desired properties.

According to an embodiment a drug delivery composition is manufactured,wherein the pharmaceutically active composition is provided as drypharmaceutically active powder. Therein, the hydrophobic matrix ishomogeneously mixed with the dry pharmaceutically active compositionpowder to form a paste-like or semi-solid drug-delivery composition.That allows arriving at a drug-delivery composition with thepharmaceutically active composition being homogeneously distributedwithin the hydrophobic matrix. Such drug-delivery compositions allowdelivering the API over prolonged time periods.

According to an embodiment a drug delivery composition is manufactured,wherein the pharmaceutically active composition powder comprisesparticles in a size range from about 100 nm to about 50 μm. Suchparticle sizes are provided applying, e.g. lyophilized proteins.

According to an embodiment a drug delivery composition is manufactured,wherein the pharmaceutically active composition is provided in a solvedstate. It is homogeneously mixed with the hydrophobic matrix to form apaste-like or semi-solid drug-delivery composition. Advantageously, atleast a solid hydrophobic substance and a liquid hydrophobic substanceare mixed simultaneously with the dissolved API to form a paste-like orsemi-solid drug-delivery composition. Optionally, the dissolved APIs canbe added to the already premixed hydrophobic substances to form thepaste-like or semi-solid drug-delivery composition.

According to an embodiment the drug-delivery composition is manufacturedas described above, wherein the pharmaceutically active compositioncomprises at least the pharmaceutically active compound and at least oneexcipient selected from the group consisting of monosaccharides,disaccharides, oligosaccharides, polysaccharides like hyaluronic acid,pectin, gum arabic and other gums, albumin, chitosan, collagen,collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin, globulin,polyaminoacids, polyurethane comprising amino acids, prolamin,protein-based polymers, copolymers and derivatives thereof, and mixturesthereof. An advantage thereof consists in further modifying releasecharacteristics of the drug-delivery paste-like or semi-solidcomposition.

According to an embodiment a drug delivery composition is manufactured,wherein the dissolved pharmaceutically active composition comprises atleast a pharmaceutically active compound without any excipients.

According to an embodiment a drug-delivery paste-like or semi-solidcomposition is manufactured, wherein the forming of the paste-like orsemi-solid drug-delivery composition includes repeated cycles ofpressing and folding, e.g. pressing and folding in an algorithmic mannerof the hydrophobic matrix itself and/or mixed with the pharmaceuticallyactive composition.

According to an embodiment, no heating to transfer the hydrophobic solidcomponent into a liquid state is used. In particular the solidhydrophobic matrix is kept throughout the mechanical treatment in anon-molten state.

According to an embodiment, active cooling is used in order to keep thehydrophobic matrix in a non-molten state throughout the pressing andfolding cycles. This approach prevents self-organization processes tooccur.

According to an embodiment the temperature of the mixture duringpressing and folding cycles can be kept below a certain temperaturevalue by cooling. Advantageously, that allows protecting susceptiblebiologically active substances such as proteins from denaturation, forinstance by keeping the temperature of the mixture below 37° C., below45° C., below 50° C., or especially below 60° C.

According to an embodiment the paste-like or semi-solid drug-deliverycomposition is manufactured by step-wise adding the dissolved APIsduring repeated pressing and folding of the mixture of the hydrophobicsubstances forming the hydrophobic matrix. It is an advantage of thatparticular embodiment that the APIs can be distributed within thehydrophobic matrix homogeneously applying that process.

According to an embodiment of the manufacturing process pressures of notmore than 10⁶ N·m⁻² are applied during the described pressing andfolding cycles.

According to an embodiment a drug-delivery paste-like or semi-solidcomposition is manufactured using APIs in dissolved state, wherein thepharmaceutically active composition is dissolved in an aqueous solutionbefore being mixed with the hydrophobic matrix.

According to an embodiment the paste-like or semi-solid drug-deliverycomposition is manufactured from APIs and hydrophobic components,wherein the pharmaceutically active composition is dissolved in anaqueous solution and is either simultaneously mixed with at least ahydrophobic solid component and a hydrophobic liquid component to form apaste-like or semi-solid drug-delivery composition; or thepharmaceutically active composition dissolved in an aqueous solution isadded after the mixing of at least a hydrophobic solid component and atleast a hydrophobic liquid component.

According to an embodiment the paste-like or semi-solid drug-deliverycomposition is manufactured from API(s) and hydrophobic components,wherein the hydrophobic matrix comprises a solid component and a liquidhydrophobic component. Therein the solid component is selected fromwaxes, fruit wax, carnauba wax, bees wax, waxy alcohols, plant waxes,soybean waxes, synthetic waxes, triglycerides, lipids, long-chain fattyacids and their salts like magnesium stearate, magnesium palmitate,esters of long-chain fatty acids, long-chain alcohols like cetylpalmitate, waxy alcohols, long-chain alcohols like cetylalcohol,oxethylated plant oils, oxethylated fatty alcohols.

According to an embodiment the pharmaceutically active composition forpreparing the paste-like or semi-solid drug-delivery composition isselected from the group consisting of: immunoglobulins, fragments orfractions of immunoglobulins, synthetic substance mimickingimmunoglobulins or fragments or fractions thereof, proteins, peptideshaving a molecular mass equal to or higher than 3.000 Dalton,ribonucleic acids (RNA), desoxyribonucleic acids (DNA), aptamers,spiegelmers, plasmids, peptide nucleic acids (PNA), steroids, andcorticosteroids, and combinations thereof.

According to an embodiment, the pharmaceutically active compound can beone or more of immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orsynthetic, semisynthetic or biosynthetic fragments or fractions thereof,chimeric, humanized or human monoclonal antibodies, Fab fragments,fusion proteins or receptor antagonists (e.g., anti TNF alpha,Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds (e.g.,anti-VEGF, anti-PDGF etc.), intracellular signaling inhibitors (e.gJAK1,3 and SYK inhibitors), peptides having a molecular mass equal to orhigher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids(DNA), plasmids, peptide nucleic acids (PNA), steroids, corticosteroids,an adrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, an antiallergic,an antiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, an antihemorrhagic, anantimyasthenic, an antiphlogistic, an antipyretic, a beta-receptorantagonist, a calcium channel antagonist, a cell, a cell differentiationfactor, a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent,a prodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue, animmunosuppressant, an immunostimulant, a mitogen, a physiological orpharmacological inhibitor of mitogens, a mineralcorticoid, a musclerelaxant, a narcotic, a neurotransmitter, a precursor of aneurotransmitter, an oligonucleotide, a peptide, a(para)-sympathicomimetic, a (para)-sympatholytic, a protein, a sedatingagent, a spasmolytic, a vasoconstrictor, a vasodilatator, a vector, avirus, a virus-like particle, a virustatic, a wound-healing substance,and combinations thereof.

According to an embodiment a drug delivery composition is manufacturedas described above, further comprising forming the drug-deliverycomposition into an applicable form. In particular, the resultinghydrophobic drug-delivery body can be transferred into the final dosageform, i.e. into bodies or micro-particles of desired shape, size andsize distribution by means of colloid forming techniques and othertechnological procedures. Colloid forming techniques comprise e.g.milling, cold extruding, emulgating, dispersing, sonificating. Thecompositions formed by the methods described herein maintain thedrug-releasing properties for a prolonged time such as weeks and months.The APIs remain protected in the paste-like or semi-solid mixture sothat their specific biological activity can be maintained. If desired,additional barrier layers can be formed around the paste-like orsemi-solid mixture.

According to an embodiment, a micro-porous membrane made fromethylene/vinyl acetate copolymer or other materials for ocular use canbe formed around the paste-like or semi-solid mixture. Further optionsinclude use of biodegradable polymers for subcutaneous and intramuscularinjection, bioerodible polysaccharides, hydrogels etc.

According to an embodiment a drug-delivery composition is provided,comprising a paste-like or semi-solid mixture comprising at least ahydrophobic matrix and a pharmaceutically active compound.

According to an embodiment a drug-delivery composition is provided,wherein the pharmaceutically active compound is dispersed in thehydrophobic matrix in particulate form.

According to an embodiment a drug-delivery composition is provided,wherein the pharmaceutically active compound is dispersed in thehydrophobic matrix in a dissolved state.

According to an embodiment a drug-delivery composition is provided,wherein the pharmaceutically active compound is dissolved in a solutioncomprising water and electrolytes.

According to an embodiment a drug-delivery composition is provided,wherein the pharmaceutically active compound is dissolved in a solutioncomprising water, electrolytes and at least one of monosaccharides,disaccharides, oligosaccharides, polysaccharides like hyaluronic acid,pectin, gum arabic and other gums, albumin, chitosan, collagen,collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin, globulin,polyaminoacids, polyurethane comprising amino acids, prolamin,protein-based polymers, copolymers and derivatives thereof, and mixturesthereof.

According to an embodiment a drug-delivery composition is provided,wherein the paste-like or semi-solid mixture has a modulus of elasticityat least of 10⁻⁴N·mm⁻².

According to an embodiment a drug-delivery composition is provided,wherein the paste-like or semi-solid mixture has a viscosity of at least100 mPa·s.

According to an embodiment a drug-delivery composition is provided,wherein the pharmaceutically active compound is selected from the groupconsisting of immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substances mimicking immunoglobulins orfragments or fractions thereof, therapeutic proteins, peptides having amolecular mass equal to or higher than 3 kDa, ribonucleic acids (RNA),desoxyribonucleic acids (DNA), plasmids, peptide nucleic acids (PNA),aptamers, spiegelmers, steroids, and corticosteroids, and combinationsthereof.

According to an embodiment a drug-delivery composition is provided,wherein the pharmaceutically active compound is selected from the groupconsisting of: immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orsynthetic, semisynthetic or biosynthetic fragments or fractions thereof,chimeric, humanized or human monoclonal antibodies, Fab fragments,fusion proteins or receptor antagonists (e.g., anti TNF alpha,Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds (e.g.,anti-VEGF, anti-PDGF etc.), intracellular signaling inhibitors (e.gJAK1,3 and SYK inhibitors), peptides having a molecular mass equal to orhigher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids(DNA), plasmids, peptide nucleic acids (PNA), steroids, corticosteroids,an adrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, an antiallergic,an antiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, an antihemorrhagic, anantimyasthenic, an antiphlogistic, an antipyretic, a beta-receptorantagonist, a calcium channel antagonist, a cell, a cell differentiationfactor, a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent,a prodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue, animmunosuppressant, an immunostimulant, a mitogen, a physiological orpharmacological inhibitor of mitogens, a mineralcorticoid, a musclerelaxant, a narcotic, a neurotransmitter, a precursor of aneurotransmitter, an oligonucleotide, a peptide, a(para)-sympathicomimetic, a (para)-sympatholytic, a protein, a sedatingagent, a spasmolytic, a vasoconstrictor, a vasodilatator, a vector, avirus, a virus-like particle, a virustatic, a wound-healing substance,and combinations thereof.

According to an embodiment a drug-delivery composition is provided,wherein the hydrophobic matrix comprises at least a hydrophobic solidcomponent and a hydrophobic liquid component, wherein the mass ratio ofthe hydrophobic solid component to the hydrophobic liquid component isbelow 2.8:1.

According to an embodiment a drug-delivery composition is provided,wherein the mass of the pharmaceutically active compound is up to 25%(w/w) of the total mass of the paste-like or semi-solid mixture.

According to an embodiment a drug-delivery composition is provided,wherein the mass of the pharmaceutically active compound is at least0.1% (w/w) of the total mass of the paste-like or semi-solid mixture.

According to an embodiment a method for delivery a drug-deliverycomposition is suggested, comprising: providing a drug-deliverycomposition comprising a paste-like or semi-solid mixture comprising atleast a hydrophobic matrix and a pharmaceutically active compound; andapplying the drug-delivery composition into a human or animal body.

According to an embodiment a method for delivery a drug-deliverycomposition is suggested, wherein applying the mixture into the human oranimal body comprises at least one of: implanting or injecting themixture into a human or animal body; intraocular injecting the mixtureinto a human, or animal body; subcutaneous injecting the mixture into ahuman, or animal body; intramuscular injecting the mixture into a human,or animal body; and intraperitoneal injecting the mixture into a human,or animal body, intravenous injecting the mixture into a human, oranimal body; inhalative or intranasal administration of the mixture intothe human or animal body.

According to typical embodiments the described treatment of thehydrophobic matrices comprises intimate mixing a solid hydrophobicmaterial and a liquid hydrophobic material with APIs to achieve anAPI-containing semi-solid material possessing superiorcontrolled-delivery properties. According to an embodiment the API(s)are added to already treated hydrophobic matrices or at a late stage oftheir treatment, i.e their intimate mixing.

Surprisingly, the mechanical treatment comprising repeated pressing andfolding cycles is slowing down the release kinetics and making therelease of the API more sustained.

The suggested method of algorithmic processes of pressing and folding isespecially suitable for formulating biologically active compounds.Biopolymers like proteins, peptides, poly- and oligonucleotides areparticularly sensitive to changes in their environment and may losetheir specific activity more readily than small-molecule APIs. SyntheticAPIs and excipients mimicking biomacromolecules may carry both anionicand cationic groups in the relevant medium or may possess differentfunctional groups in variable density on a molecular backbone.

The suggested approach combines the benefit of initial thorough mixingof the hydrophobic matrix with the controlled-release of microparticlesbut does not suffer from the disadvantages of any of these formulationswhen applied alone.

The matrix formed by the mechanical treatment of solid and liquidcomponents is typically a hydrophobic matrix but can also include asmall amount of hydrophilic excipients/ingredients.

The suggested method is different from other approaches in that thepaste-like or semi-solid composition is formed by mechanical treatment,i.e. repeated pressing and folding cycles. Particularly, according to anembodiment, the paste-like or semi-solid composition is formed bykneading which is an example of an algorithmic pressing-folding cycle.

According to an embodiment, the pharmaceutically active substance or APIis provided as dry pharmaceutically active compound powder. The solidand liquid hydrophobic components are homogeneously mixed with eachother with or without the presence of the dry pharmaceutically activecompound to prepare a sustained delivery body.

The mechanical procedures can include repeatedly pressing and foldingthe mixture of the hydrophobic solid and liquid materials. Themechanical procedures may start with pressing to bring the mass into amore flat shape and then folding the mass, for example by a blade orother suitable means. The folded mass is then pressed again. Byrepeating these processes a better distribution of the pharmaceuticallyactive compound (API) throughout the matrix can be achieved.

The API(s) can be added to the treated system during all phases of thepreparation process, and, according to an embodiment, at a late stageafter forming an established excipient matrix system. The late additionof the APIs to the already homogenized mixture of hydrophobicconstituents minimizes the influence of mechanical mixing on the APIs.

According to an embodiment, the mechanical processing of the mass canalso include other processes such as rolling, extrusion from or througha nip between rolls.

The force acting on the mass may be limited to avoid excessivemechanical impact, which might affect the API. According to anembodiment, a pressure of not more than 10⁶ N·m⁻² is applied to themass. According to further embodiments, a pressure of not more than5×10⁵N·m⁻² is applied to the mass.

According to an embodiment, the mechanical treatment of the hydrophobicmatrix components yields a homogeneous distribution of the API withinthe matrix.

The APIs may be provided as dry component or the APIs may be dissolvedin an aqueous solution.

According to an embodiment, the APIs can be provided in particulate formsuch as micro- or nano-particles. Suitable particle sizes range fromabout 100 nm to about 50 μm, particularly from about 500 nm to about 30μm, and more particularly from about 1 μm to about 10 μm.

In the approach described herein, the controlled mixing of thecomponents into a homogeneous mass transforms the preparation into apaste- or dough-like consistency, which is appropriate for theproduction of slow release compositions. The processes according to oneembodiment include mixing of all solid hydrophobic ingredients in afirst step followed by adding the liquid hydrophobic matrix component togenerate the paste-like or semi-solid consistency during mechanicaltreatment. The APIs is added, for instance as a dry powder into thepaste like mass and the mechanical treatment is continued to gainhomogeneity of the paste like mass.

According to an embodiment, APIs can be small molecules, peptides,proteins, therapeutic proteins, antibodies, antigens, enzymes, receptorligands, nucleotides or nucleotide analogs, oligonucleotides andoligonucleotide analogs (aptamers and spiegelmers), genes or gene-likespecies, viruses, virus-like particles, sugars or polysaccharides ortheir analogs, or any other physical composition such as livingorganelles, cells, or tissue constituents.

According to an embodiment excipients can include almost any member ofthese same classes of species. They often act as buffer, filler, binder,osmotic agent, lubricant, or fulfill similar functions. Polyampholytesare multiply-charged polymers, which bear both anionic and cationicgroups in the relevant medium, e.g. in an aqueous solution. The variousclasses and types of APIs, excipients, polymers, and polyampholytes arefamiliar to those skilled in the art of drug delivery.

According to an embodiment, an example for an excipient can be a sugarselected from monosaccharides, disaccharides, oligosaccharides,polysaccharides. The excipients can further comprise albumin, chitosan,collagen, collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin,globulin, polyaminoacids, polyurethane comprising amino acids, prolamin,protein-based polymers, copolymers and derivatives thereof, and mixturesthereof.

According to an embodiment, the pharmaceutically active compound can beone or more of immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orsynthetic, semisynthetic or biosynthetic fragments or fractions thereof,chimeric, humanized or human monoclonal antibodies, Fab fragments,fusion proteins or receptor antagonists (e.g., anti TNF alpha,Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds (e.g.,anti-VEGF, anti-PDGF etc.), intracellular signaling inhibitors (e.gJAK1,3 and SYK inhibitors), peptides having a molecular mass equal to orhigher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids(DNA), plasmids, peptide nucleic acids (PNA), steroids, corticosteroids,an adrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, an antiallergic,an antiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, an antihemorrhagic, anantimyasthenic, an antiphlogistic, an antipyretic, a beta-receptorantagonist, a calcium channel antagonist, a cell, a cell differentiationfactor, a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent,a prodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue, animmunosuppressant, an immunostimulant, a mitogen, a physiological orpharmacological inhibitor of mitogens, a mineralcorticoid, a musclerelaxant, a narcotic, a neurotransmitter, a precursor of aneurotransmitter, an oligonucleotide, a peptide, a(para)-sympathicomimetic, a (para)-sympatholytic, a protein, a sedatingagent, a spasmolytic, a vasoconstrictor, a vasodilatator, a vector, avirus, a virus-like particle, a virustatic, a wound-healing substance,and combinations thereof.

According to an embodiment, the drug-delivery composition can be broughtinto an implantable form to form an implantable drug-deliveryformulation with controlled-release kinetics. According to the novelproposed approach the hydrophobic matrix itself can be comprised ofnatural waxes, fats and oils as well as synthetic substances orchemically modified natural waxes, fats and oils. The implantabledrug-delivery formulation can be activated.

The present invention encompasses not only the use of pure hydrophobicmatrix materials but can comprise also minor amounts of aqueoussolutions. The method and composition described herein can use anysubstance which can exert a therapeutic effect, including smallmolecules, synthetic or biological macromolecules such as peptides,proteins, nucleic acids, oligonucleotides, carbohydrates, and othersfamiliar to one skilled in the art.

The hydrophobic materials of the present invention can optionally belabeled with any of a wide variety of agents, which are known to thoseskilled in the art. As examples, dyes, fluorophores, chemiluminescentagents, isotopes, metal atoms or clusters, radionuclides, enzymes,antibodies, or tight-binding partners such as biotin and avidin can allbe used to label the hydrophobic drug-delivery composition fordetection, localization, imaging, or any other analytical or medicalpurpose. The hydrophobic delivery composition, particularly a liquidcomponent of the matrix, can also optionally be conjugated with a widevariety of molecules in order to modify its function, modify itsstability, or further modify the rate of release of the APIs. Asexamples, the drug-delivery composition can be coated with a covalently-or non-covalently-attached layer of a species such as small molecules,hormones, peptides, proteins, phospholipids, polysaccharides, mucins, orbiocompatible polymers such polyethylene glycol (PEG), dextran, or anyof a number of comparable materials. The wide range of materials, whichcan be used in this fashion, and the methods for accomplishing theseprocesses, are well known to those skilled in the art.

The various starting components such as the hydrophobic matrix and theAPIs can be further manipulated and processed using a wide variety ofmethods, processes, and equipment familiar to one skilled in the art.For example, the hydrophobic matrix components can be thoroughly mixedusing any of a number of known methods and equipment, such astrituration with a mortar and pestle or blending in a Patterson-Kelleytwin-shell blender, before adding the API. Furthermore, a wide varietyof shapes, sizes, morphologies, and surface compositions of thedrug-delivery composition can be formed. For example, micro-particles orcylindrical bodies with different aspect ratios can be prepared by meansof mechanical milling, molding, and extruding or similar processes ofthe paste-like or semi-solid or even semi-solid material. The resultingparticles can be further treated to prepare them for specificapplications such as e.g. drug delivery systems. As another example,transforming the mixture, paste or mass into micro-particles or bodiesby means of cold extrusion, cooled pressure homogenization, molding,and/or other such well-established procedures can yield a wide range offinal products. As another example, the polymeric drug-deliverycomposition can be squeezed through a sieving disk (i.e. a die)containing predefined pores or channels with uniform pore geometry anddiameter by an extrusion process.

According to an embodiment, the paste-like or semi-solid mixturedrug-delivery composition has a modulus of elasticity of at least 10⁻⁴N·mm⁻². According to an embodiment, the paste-like or semi-solid mixturedrug-delivery composition has a modulus of elasticity of at least 10⁻³N·mm², and particularly 10⁻² N·mm⁻², and more particularly 10⁻¹ N·mm⁻².

According to an embodiment, the paste-like or semi-solid mixtures has aviscosity of not more than 500 Pa·s, and particularly of not more than250 Pa·s. According to an embodiment, the paste-like or semi-solidmixtures has a viscosity of not less than few mPa·s, for example 100mPa·s, and particularly of not less than 1 Pa·s.

According to an embodiment, the pharmaceutical active compound isprovided as powder having particles in a range from about 100 nm toabout 50 μm, particularly from about 500 nm to about 30 μm, and moreparticularly from about 1 μm to about 10 μm

Specific examples are described below. The “UV 280 nm method” mentionedtherein comprises the detection of proteins by their absorption at 280nm in physiologically isotonic salt solution (PBS) against a blank usingan UV/VIS spectrophotometer and quartz cuvettes and using calibrationsfor different APIs and different concentrations.

Example 1

72 mg of an antibody 2 (of gamma globulin type) solution (25 mg/ml) wasadded to 170 mg of cetyl alcohol and 50 mg of castor oil. This mixturewas mechanically treated and mixed using an agate mortar and pestle for7 minutes. Finally, a spherical particle was formed by hand and added to3.3 g of an isotonic sodium chloride solution containing 0.01% of sodiumazide. The release of antibody 1 was determined spectroscopically by theUV 280 nm method under no-sink conditions (see FIG. 1, sample 1).

Example 2

72 mg of a lyophilized antibody 3 (of gamma globulin type) was added to90 mg of cetyl alcohol and 50 mg of castor oil. This mixture wasmechanically treated and mixed using an agate mortar and pestle for 5minutes. Finally, a spherical particle was formed by hand and added to10 g of an isotonic sodium chloride solution containing 0.01% of sodiumazide. The release of antibody 3 was determined spectroscopically by theUV 280 nm method under no-sink conditions (see FIG. 1, sample 2).

Example 3

100 mg of a solution of antibody 1 (of gamma globulin type) (50 mg/ml)was added to 95 mg of cetyl alcohol and 75 mg of castor oil. Thismixture was mechanically treated and mixed using an agate mortar andpestle for 7 minutes. Finally, a spherical particle was formed by handand added to 6.4 g of an isotonic sodium chloride solution containing0.01% of sodium azide. The release of antibody 2 was determinedspectroscopically by the UV 280 nm method under no-sink conditions. Thebiological activity of the last measured concentration value wasmeasured by ELISA as given in brackets (see FIG. 1, sample 3).

Example 4

76 mg of an antibody solution antibody 2 (of gamma globulin type) (25mg/ml) was added to 170 mg of cetyl alcohol and 45 mg of soybean oil.This mixture was mechanically treated using an agate mortar and pestlefor 6 minutes. Finally, a spherical particle was formed by hand andadded to 3.3 g of a phosphate buffered solution containing 0.01% ofsodium azide. The release of antibody 1 was determined spectroscopicallyby the UV 280 nm method under sink conditions. The biological activityof the last measured concentration value was measured by ELISA as givenin brackets (see FIG. 1, sample 4).

Example 5

101 mg of an antibody solution antibody 1 (of gamma globulin type) (25mg/ml) was added to 101 mg of cetyl alcohol and 80 mg of soybean oil.This mixture was mechanically treated using an agate mortar and pestlefor 7 minutes. Finally, a spherical particle was formed by hand andadded to 5.7 g of a phosphate buffered solution containing 0.01% ofsodium azide. The release of antibody 2 was determined spectroscopicallyby the UV 280 nm method under sink conditions. The biological activityof the last measured concentration value was measured by ELISA as givenin brackets (see FIG. 1, sample 5).

Example 6

116 mg of an antibody solution antibody 2 (of gamma globulin type) (25mg/ml) was added to 170 mg of magnesium stearate and 78 mg of soybeanoil. This mixture was mechanically treated using an agate mortar andpestle for 7 minutes. Finally, a spherical particle was formed by handand added to 5.7 g of a phosphate buffered solution containing 0.01% ofsodium azide. The release of antibody 1 was determined spectroscopicallyby the UV 280 nm method under sink conditions. The biological activityof the last measured concentration value was measured by ELISA as givenin brackets (see FIG. 1, sample 6).

Example 7

98 mg of an antibody solution antibody 1 (of gamma globulin type) (50mg/ml) was added to 97 mg of magnesium stearate and 79 mg of soybeanoil. This mixture was mechanically treated using an agate mortar andpestle for 7 minutes. Finally, a spherical particle was formed by handand added to 4.2 g of a phosphate buffered solution containing 0.01% ofsodium azide. The sample was stored at 37° C. for the experimentalperiod. The release of antibody was determined spectroscopically by theUV 280 nm method under sink conditions. The biological activity of thelast measured concentration value was measured by ELISA as indicated inbrackets (see FIG. 2).

The difference between mechanically treated drug delivery matrices andthe self-organized ones have been studied in example 8 below and isillustrated in FIG. 3.

Example 8 Self Organization

13 mg of a lyophilized antibody 3 (of gamma globulin type) was added to93 mg of cetyl palmitate and 48 mg of castor oil. This mixture washomogenized by heating under stirring using a water bath and a magneticstirrer to form a molten mass (45° C.). After cooling down the obtainedsolid mass was added to 3.0 g of a phosphate buffered solutioncontaining 0.1% of sodium azide. The release of antibody 3 wasdetermined spectroscopically by the UV 280 nm method under sinkconditions (see FIG. 3, sample 8).

Example 9 Mechanical Treatment

11 mg of a lyophilized antibody 3 (of gamma globulin type) was added to83 mg of cetyl palmitate and 38 mg of castor oil. This mixture wasmechanically treated and mixed using an agate mortar and pestle for 7minutes. Finally, a spherical particle was formed by kneading for 1minute and added to 3.0 g of a phosphate buffered solution containing0.1% of sodium azide. The release of antibody 3 was determinedspectroscopically by the UV 280 nm method under sink conditions (seeFIG. 3, sample 9).

1. A method for manufacturing a drug-delivery composition, comprising:providing at least a pharmaceutically active composition; providing ahydrophobic matrix; and mixing the hydrophobic matrix and thepharmaceutically active composition to form a paste-like or semi-soliddrug-delivery composition.
 2. The method according to claim 1, whereinproviding the hydrophobic matrix comprises mixing of at least ahydrophobic solid component and a hydrophobic liquid component.
 3. Themethod according to claim 1, further comprising: providing thepharmaceutically active composition as dry pharmaceutically activecomposition powder; and homogeneous mixing the hydrophobic matrix withthe dry pharmaceutically active composition powder to form thepaste-like or semi-solid drug delivery composition.
 4. The methodaccording to claim 1, further comprising: providing the pharmaceuticallyactive composition in a dissolved state; and homogeneous mixing thehydrophobic matrix with the dissolved pharmaceutically activecomposition to form the paste-like or semi-solid drug-deliverycomposition.
 5. The method according to claim 1, wherein thepharmaceutically active composition comprises at least apharmaceutically active compound and at least one excipient selectedfrom the group consisting of monosaccharides, disaccharides,oligosaccharides, polysaccharides like hyaluronic acid, pectin, gumarabic and other gums, albumin, chitosan, collagen,collagen-n-hydroxysuccinimide, fibrin, fibrinogen, gelatin, globulin,polyaminoacids, polyurethane comprising amino acids, prolamin,protein-based polymers, copolymers and derivatives thereof, and mixturesthereof.
 6. The method according to claim 1, wherein thepharmaceutically active composition comprises at least apharmaceutically active compound without any excipients.
 7. The methodaccording to claim 1, wherein the forming of the paste-like orsemi-solid drug-delivery composition includes repeated cycles ofpressing and folding, in an algorithmic manner, of the mixture of thehydrophobic matrix and the pharmaceutically active composition.
 8. Themethod according to claim 4, wherein the dissolved pharmaceuticallyactive composition is added step-wise during mixing comprising repeatedpressing and folding of the mixture of the hydrophobic matrix and thepharmaceutically active composition.
 9. The method according to claim 7,wherein the pressing applies a pressure of not more than 10⁶ N·m⁻². 10.The method according to claim 1, wherein the pharmaceutically activecomposition is dissolved in an aqueous solution before being mixed withthe hydrophobic matrix.
 11. The method according to claim 1, furthercomprising one of: simultaneous mixing of at least a hydrophobic solidcomponent, a hydrophobic liquid component, and the pharmaceuticallyactive composition dissolved in an aqueous solution to form thepaste-like or semi-solid drug-delivery composition; and mixing of atleast a hydrophobic solid component and a hydrophobic liquid componentto form the hydrophobic matrix, and adding the pharmaceutically activecomposition dissolved in an aqueous solution to the hydrophobic matrixto form the paste-like or semi-solid drug-delivery composition.
 12. Themethod according to claim 3, wherein the pharmaceutical activecomposition powder comprises particles in a size range from about 100 nmto about 50 μm.
 13. The method according to claim 1, wherein thehydrophobic matrix comprises a solid component and a liquid hydrophobiccomponent, wherein the solid component is selected from waxes, fruitwax, carnauba wax, bees wax, waxy alcohols, plant waxes, soybean waxes,synthetic waxes, triglycerides, lipids, long-chain fatty acids and theirsalts like magnesium stearate, magnesium palmitate, esters of long-chainfatty acids, long-chain alcohols like cetyl palmitate, waxy alcohols,long-chain alcohols like cetylalcohol, oxethylated plant oils,oxethylated fatty alcohols, and wherein the liquid hydrophobic componentis selected from plant oils, castor oil, jojoba oil, soybean oil,silicon oils, paraffin oils, and mineral oils, cremophor, oxethylatedplant oils, oxethylated fatty alcohols.
 14. The method according toclaim 1, wherein the pharmaceutically active composition comprises apharmaceutically active compound selected from the group consisting ofimmunoglobulins, fragments or fractions of immunoglobulins, syntheticsubstance mimicking immunoglobulins or fragments or fractions thereof,proteins peptides having a molecular mass equal to or higher than 3 kDa,ribonucleic acids (RNA), desoxyribonucleic acids (DNA) includingaptamers and spiegelmers, plasmids, peptide nucleic acids (PNA),steroids, and corticosteroids.
 15. The method according to claim 1,wherein the pharmaceutically active composition comprises apharmaceutically active compound selected from the group consisting ofimmunoglobulins, fragments or fractions of immunoglobulins, syntheticsubstance mimicking immunoglobulins or synthetic, semisynthetic orbiosynthetic fragments or fractions thereof, chimeric, humanized orhuman monoclonal antibodies, Fab fragments, fusion proteins or receptorantagonists (e.g., anti TNF alpha, Interleukin-1, Interleukin-6 etc.),antiangiogenic compounds (e.g., anti-VEGF, anti-PDGF etc.),intracellular signaling inhibitors (e.g JAK1,3 and SYK inhibitors),peptides having a molecular mass equal to or higher than 3 kDa,ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,peptide nucleic acids (PNA), steroids, corticosteroids, anadrenocorticostatic, an antibiotic, an antidepressant, an antimycotic, a[beta]-adrenolytic, an androgen or antiandrogen, an antianemic, ananabolic, an anaesthetic, an analeptic, an antiallergic, anantiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, an antihemorrhagic, anantimyasthenic, an antiphlogistic, an antipyretic, a beta-receptorantagonist, a calcium channel antagonist, a cell, a cell differentiationfactor, a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent,a prodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue, animmunosuppressant, an immunostimulant, a mitogen, a physiological orpharmacological inhibitor of mitogens, a mineralcorticoid, a musclerelaxant, a narcotic, a neurotransmitter, a precursor of aneurotransmitter, an oligonucleotide, a peptide, a(para)-sympathicomimetic, a (para)-sympatholytic, a protein, a sedatingagent, a spasmolytic, a vasoconstrictor, a vasodilatator, a vector, avirus, a virus-like particle, a virustatic, a wound-healing substance,and combinations thereof.
 16. The method according to claim 1, furthercomprising: forming the drug-delivery composition into an applicableform.
 17. A drug-delivery composition, comprising: a paste-like orsemi-solid mixture comprising at least a hydrophobic matrix and apharmaceutically active compound.
 18. The drug-delivery compositionaccording to claim 17, wherein the pharmaceutically active compound isdispersed in the hydrophobic matrix in particulate form.
 19. Thedrug-delivery composition according to claim 17, wherein thepharmaceutically active compound is dispersed in the hydrophobic matrixin a dissolved state.
 20. The drug-delivery composition according toclaim 19, wherein the pharmaceutically active compound is dissolved in asolution comprising water and electrolytes.
 21. The drug-deliverycomposition according to claim 19, wherein the pharmaceutically activecompound is dissolved in a solution comprising water, electrolytes andat least one of monosaccharides, disaccharides, oligosaccharides,polysaccharides like hyaluronic acid, pectin, gum arabic and other gums,albumin, chitosan, collagen, collagen-n-hydroxysuccinimide, fibrin,fibrinogen, gelatin, globulin, polyaminoacids, polyurethane comprisingamino acids, prolamin, protein-based polymers, copolymers andderivatives thereof, and mixtures thereof.
 22. The drug-deliverycomposition according to claim 17, wherein the paste-like or semi-solidmixture has a modulus of elasticity at least of 10⁻⁴N·mm⁻².
 23. Thedrug-delivery composition according to claim 17, wherein the paste-likeor semi-solid mixture has a viscosity of at least 100 mPa·s.
 24. Thedrug-delivery composition according to claim 17, wherein thepharmaceutically active compound is selected from the group consistingof immunoglobulins, fragments or fractions of immunoglobulins, syntheticsubstance mimicking immunoglobulins or fragments or fractions thereof,proteins, peptides having a molecular mass equal to or higher than 3kDa, ribonucleic acids (RNA), desoxyribonucleic acids (DNA), plasmids,peptide nucleic acids (PNA), aptamers, spiegelmers, steroids, andcorticosteroids.
 25. The drug-delivery composition according to claim17, wherein the pharmaceutically active compound is selected from thegroup consisting of: immunoglobulins, fragments or fractions ofimmunoglobulins, synthetic substance mimicking immunoglobulins orsynthetic, semisynthetic or biosynthetic fragments or fractions thereof,chimeric, humanized or human monoclonal antibodies, Fab fragments,fusion proteins or receptor antagonists (e.g., anti TNF alpha,Interleukin-1, Interleukin-6 etc.), antiangiogenic compounds (e.g.,anti-VEGF, anti-PDGF etc.), intracellular signaling inhibitors (e.gJAK1,3 and SYK inhibitors), peptides having a molecular mass equal to orhigher than 3 kDa, ribonucleic acids (RNA), desoxyribonucleic acids(DNA), plasmids, peptide nucleic acids (PNA), steroids, corticosteroids,an adrenocorticostatic, an antibiotic, an antidepressant, anantimycotic, a [beta]-adrenolytic, an androgen or antiandrogen, anantianemic, an anabolic, an anaesthetic, an analeptic, an antiallergic,an antiarrhythmic, an antiarterosclerotic, an antibiotic, anantifibrinolytic, an anticonvulsive, an antiinflammatory drug, ananticholinergic, an antihistaminic, an antihypertensive, anantihypotensive, an anticoagulant, an antiseptic, an antihemorrhagic, anantimyasthenic, an antiphlogistic, an antipyretic, a beta-receptorantagonist, a calcium channel antagonist, a cell, a cell differentiationfactor, a chemokine, a chemotherapeutic, a coenzyme, a cytotoxic agent,a prodrug of a cytotoxic agent, a cytostatic, an enzyme and itssynthetic or biosynthetic analogue, a glucocorticoid, a growth factor, ahaemostatic, a hormone and its synthetic or biosynthetic analogue, animmunosuppressant, an immunostimulant, a mitogen, a physiological orpharmacological inhibitor of mitogens, a mineralcorticoid, a musclerelaxant, a narcotic, a neurotransmitter, a precursor of aneurotransmitter, an oligonucleotide, a peptide, a(para)-sympathicomimetic, a (para)-sympatholytic, a protein, a sedatingagent, a spasmolytic, a vasoconstrictor, a vasodilatator, a vector, avirus, a virus-like particle, a virustatic, a wound-healing substance,and combinations thereof.
 26. The drug-delivery composition according toclaim 17, wherein the hydrophobic matrix comprises at least ahydrophobic solid component and a hydrophobic liquid component, whereinthe mass ratio of the hydrophobic solid component to the hydrophobicliquid component is below 2.8:1.
 27. The drug-delivery compositionaccording to claim 17, wherein the mass of the pharmaceutically activecompound is up to 25% (w/w) of the total mass of the paste-like orsemi-solid mixture.
 28. The drug-delivery composition according to claim17, wherein the mass of the pharmaceutically active compound is at least0.01% (w/w) of the total mass of the paste-like or semi-solid mixture.29. A method for delivery a drug-delivery composition, comprising:providing a drug-delivery composition comprising a paste-like orsemi-solid mixture comprising at least a hydrophobic matrix and apharmaceutically active compound; and applying the drug-deliverycomposition into a human or animal body.
 30. The method of claim 29,wherein applying the mixture into the human or animal body comprises atleast one of: implanting or injecting the mixture into a human or animalbody; intraocular injecting the mixture into a human, or animal body;subcutaneous injecting the mixture into a human, or animal body;intramuscular injecting the mixture into a human, or animal body;intraperitoneal injecting the mixture into a human, or animal body;intravenous injecting the mixture into a human, or animal body;inhalative administering the mixture into a human, or animal body; andintranasal administering the mixture into a human, or animal body.